Preparation of anabolic agents



United States Patent 3,087,942 PREPARATION OF ANABOLIC AGENTS KlausBriickner, Klaus Irmscher, and Josef Gillissen,

Darmstarlt, Germany, assignors to E. Merck Aktiengesellschaft,Darmstadt, Germany No Drawing. Filed Oct. 25, 1961, Ser. No. 147,469

Claims priority, application Germany Oct. 29, 1960 4 Claims. (Cl.260397.4)

This invention relates to the preparation of novel steroid compoundshaving a high anabolic activity and a low androgenic activity.

An anabolic agent, sometimes called a myotrephic agent, promotes storageof protein and generally stimulates tissues. These agents are useful forthe treatment of persons debilitated by various metabolic and endocrinedisorders. Unfortunately, though, anabolicagents usually also exhibit asignificant androgenic effect, and, therefore, debilitated femalescannot be treated with these anabolic agents without the danger ofimparting masculine characteristics to the females.

A classical example of an anabolic agent having an excessive androgenicactivity is the compound testosterone.

A great deal of effort has been expended to upgrade theanabolic-androgenic activity of testosterone, but usually with nooutstanding success. For example, in a paper by R. M. Dodson and RobertC. Tweit, in the Journal of the American Chemical Society, volume 81,pages 12-24 (1959), there is reported a modification of testosterone bythe introduction of a 7- as well as a 1- acetylthio group into bothtestosterone, the l 7-ester thereof, and 4-androstene-3,l7-dione. These7- and l-acetylthio derivatives were tested and the results indicated adecrease in both the androgenic and anabolic activities of these.steroids. In contrast to these results, it is to be appreciated thatmodified testosterones are sought which exhibit a decreased androgenicactivity, but simultaneously either maintaining or increasing theanabolic activity.

The object of this invention, therefore, is to provide new steroidcompounds having a high anabolic activity and a low androgenic activity.

Upon further study of the specification and appended claims, otheradvantages and objects of the present invention will become apparent.

To attain the objects of this invention, it has been unexpectedlydiscovered that by the incorporation of an acetylthio group in the 70:.or lot positions, or both, in 17a-methyl-testosterones, there areobtained steroids which exhibit a high anabolic effect and a lowandrogenic effect. These novel derivatives, capable of oraladministration, exhibit an increased anabolic effect and a substantiallyreduced androgenic effect, as compared to the unsubstituted17a-methyl-testosterone.

These excellent physiological properties of the new derivatives arequite surprising in view of the aforementioned Dodson and Tweit paperwhich teaches that the introduction of a 7- and l-acetylthio group intotestosterone and the l7-esters thereof, result in a decrease in theanabolic effect of the parent compound. This invention, on the otherhand, teaches that there is an increase in the anabolic effect when the7:1- and lot-acetylthio groups are introduced into the17a-methyl-testosterones.

Furthermore, it was discovered that upon the introduction of the 70candlot-acetylthio groups to the 16- methylene derivatives ofl7-u-methyl-testosterones an even further reduction in the androgeniceffect is obtained, while the anabolic effect is maintained constant, ascompared to the corresponding substitution product which does not have a16-methylene group.

3,087,942 Patented Apr. 30, 1963 The novel compounds of this inventionconform to the following structural generic formula:

wherein R is selected from the group consisting of: CH CO-S andhydrogen, and wherein at least one R represents -CH CO--S; and wherein Xis selected from the group consisting of: 1H,H and methylene.

As typical examples of the novel steroids of this invention, there areincluded:

7 u-acetylthiod 7 a-methyl-testosteronela-acetylthio-l7a-methyl-testosterone '1a,7u-di-acetylthiol7a-methyl-testosterone7a-acetylthio-l6-methylene-l7a-methyl-testosterone -l aacetylthiol-6-methylene-l 7a-methyl-testo sterone1a,7a-di-acetylthio-lo-methylene-17a-methyl-testosterone To demonstratethe improved anabolic-androgenic ratios of the compound of thisinvention, reference is made to the following table, wherein theanabolic-androgenic ratios of the 7aand loc-acetylthio substitutionprodnets are compared to the same compound devoid of the Theanabolic-androgenic ratios thus obtained are compared to the well knownanabolic compound methyltestosterone, the ratio of which is l. Thetrials were conducted according to the commonly used method ofHershberger et al. described in proceedings of the Society forExperimental Biology and Medicine, vol. 83, page 1-75 (1953), the dosebeing 1 or ll) mg. per animal.

The novel compounds of this invention are particularly efiicaciousanabolic agents which can be administered perorally, preferably in 5 mg.doses. These drugs may be manufactured in the form of tablets, pills,dragees, solutions or emulsions with the aid of the usual pharmaceuticalauxiliary agents and excipients. The preferred concentration of thesolutions is 1 mg./cc.

The novel compounds of this invention can be produced by conventionalmethods from 17a-methyl-testosterone derivatives which are unsaturatedin the .1,2.- and/ or the 6,7-positions. These aforesaid raw materialsare reacted with thioacetic acid under conventional conditions.Preferably it is advantageous to conduct the reaction in contact withultra-violet radiation, and in the presence of an inert solvent, such asbenzene, dioxane, toluene, carbon tetrachloride, etc.

It is to be appreciated that the foregoing brief description of themethod of producing the novel steroids of this invention is adequate toteach a steroid chemist skilled in the art how to produce the novelcompounds of this invention.

The following examples, therefore, are merely preferred specificembodiments of this invention, and are not intended to be limitative ofthe specification and appended claims.

Example 1 7 g. 6-dehydro-17a-methyl-testosterone are heated in 20 ml.thioacetic acid on a steam bath for 1.5 hours. The thioacetic acid isthereafter extracted by vacuum and the residue is crystallized frommethanol. The 7 a-acetylthio --17a methyl testosterone melts at 162-163C.; max' l,

Eli... 500; (a)n-69.3 C.

Example 2 4 g. 17a-methyl-1,4,6-androstatriene-l 7fi-ol-3-one are boiledin 12 ml. thioacetic acid under reflux for 1 hours. This reactionmixture is thereafter concentrated in vacuum to dryness and the1a,7a-di-acetylthio-17amethyl-testosterone is crystallized from theresidue after treatment with methanol; melting point 202-204" C.; (u)74.6 C. (dioxane); 7\ 237.5 ma,

Example 3 2.9 g. l-dehydro-l7a-methyl-testosterone are dissolved in ml.thioacetic acid and are boiled under reflux for 1.5 hours. The reactioncomposition is thereafter concentrated in vacuum and the residue iscrystallized from ether. The obtained 1a-acetylthio17a-methyltestosterone melts at 160a161 C.; (a) +98 (Chlf.); max l",

Ell... 4

Example 4 3.25 g. 1-dehydro-16-methy1ene-17a methyl-testosterone areboiled in 15 ml. thioacetic acid under reflux for 1%, hours. Thesolution is thereafter concentrated in vacuum, the residue iscrystallized from ether/petroleum ether, and thel-acetylthio-16-methylene-17a-methyl-testosterone is purified byrecrystallization from ether. The melting point is 154-155 C. Theproduct melts after 4 further recrystallization at 157160 C.; (oc +30 C.(dioxane); A 240 ma,

El'fi 450 Example 5 According to Example 1, the7a-acetylthio-16-methylene-l7a-methyl-testosterone is produced from6-dehydro- 16-methylene-17a-methyl-testosterone. Melting point 147149C.; A 238 m El'fi' 500; (a)n149.3 (dioxane) Example 6 According toExample 2, the 1a,7a-di-acetylthio-l6- methylene-17a-methyl-testosteroneis produced from l6- methylene-17a-methyl-1,4,6-androstatriene-3-one-175ol. Melting point 194-196 C.; A 238 ma,

lli... 1

References Cited in the file of this patent UNITED STATES PATENTS2,859,222 Dodson et al Nov. 4, 1958 2,875,215 Dodson et a1 Feb. 24, 19592,929,763 Wettstein et a1 Mar. 22, 1960 OTHER REFERENCES Iriarte et al.:81 J.A.C.S. 436-438 (1959).

1. 1A-7A-DIACETYLTHIO-17A-METHYL-TESTOSTERONE,